Up to 60% of patients with bipolar disorder abuse drugs and/or alcohol. This represents a major public health concern as comorbid substance abuse has been associated with poor outcome. Specific treatment interventions for this large patient population are undeveloped, in large part because how substance abuse influences the course of bipolar disorder is unknown. Recently, the phenomenon of behavioral sensitization has been suggested to represent a model of the development and longitudinal course of bipolar disorder, particularly with regard to the influence of stressors. As comorbid substance abuse is a particularly common and important psychosocial and biological stressor, this model provides a framework for examining the effects of drug and alcohol abuse on the course of bipolar disorder. Specifically, this model predicts that comorbid substance abuse will increase the frequency, duration, and severity of affective episodes. These effects are hypothesized to be clinically observable in patients with substance abuse comorbidity as increased rates of rapid and continuous cycling, mixed-state episodes, and mood-incongruent psychosis. The objectives of this study are to prospectively and longitudinally examine these hypotheses to clarify how substance abuse effects the course of bipolar illness. To achieve this objective, 120-140 patients will be prospectively recruited at the time of their first manic episode from the psychiatric inpatient and emergency services of the University of Cincinnati Hospital. Patients will be carefully evaluated symptomatically, diagnostically, and functionally using structured and semi-structured interviews. The assessments of the bipolar illness and substance abuse will be independently obtained. Careful distinction will be made between substance abuse and substance dependence. Patients will be re-evaluated at 4 month intervals for up to 5 years. Multivariate regression and survival analysis models will be used to evaluate the relationships between substance abuse and operationally defined course and outcome measures. The innovative aspects of this project are the prospective and longitudinal assessment of the interaction of drug and alcohol abuse and dependence on clinical variables related to the course of bipolar disorder following a first manic episode. Specific hypotheses are examined that have been developed from consideration of neurobiological model of behavioral sensitization.